Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients. Keywords: histone methyltransferase DOT1L, H3K79 methylation, psammaplin A analog (PsA-3091), triple-negative breast cancer, metastasis, epithelial-mesenchymal transition (EMT)